Angiopoietic factors and retinopathy in pregnancies complicated with Type 1 diabetes.

AIMS: To evaluate the role of systemic angiopoietic factors in the progression of diabetic retinopathy during pregnancy. METHODS: In a prospective study of 26 pregnant women with diabetes and eight non-diabetic pregnant women, retinopathy was graded from fundus photographs. Plasma levels of angiopoietin-1, angiopoietin-2, human vascular endothelial growth factor A (hVEGF-A), and total soluble receptor of vascular endothelial growth factor (sVEGF) receptor-1 were measured during the first and third trimester and 3 months postpartum. RESULTS: In diabetic women, levels of angiopoietin-2 were 26.5 ng/ml (12.1-47.7) (median and range) during the first trimester, 2.9 ng/ml (0.6-3.5) during the third trimester, and 0.5 ng/ml (0.3-0.7) 3 months postpartum, compared with 44.3 (38.3-61.9), 5.7 (3.1-8.4) and 0.9 (0.6-4.9) ng/ml, respectively, in non-diabetic women (P = 0.002 between groups). Levels of angiopoietin-1 and sVEGF receptor-1 did not differ between the groups. Postpartum hVEGF-A levels were lowest in women with progression of retinopathy. In logistic regression analyses, progression of retinopathy during pregnancy was not explained by the levels of the angiopoietic factors. CONCLUSIONS: The circulating levels of angiopoietic factors in pregnant diabetic women were either lower than (Ang-2) or similar to (Ang-1, hVEGF-A, VEGFR-1) those levels observed in non-diabetic pregnant women. The levels of angiopoietic factors measured here appear not to be connected with the progression of retinopathy during pregnancy.

Fetal shoulder measurements by fast and ultrafast MRI techniques.

The purpose of this study was to evaluate magnetic resonance imaging (MRI) of fetal shoulder measurements of fetuses with suspected macrosomia. The actual fetal shoulder measurements made immediately after birth were compared with measurements obtained by fast and ultrafast MRI techniques antepartum. Eight singleton diabetic pregnant mothers underwent MRI examination with fast imaging in steady-state precession (TrueFISP) and spin-echo (SE) and gradient-echo (GE) echo-planar (EPI) sequences to show the fetal shoulder width. The actual shoulder width was measured immediately postpartum by a neonatologist. There was a statistically significant correlation between the MRI measurements and the actual shoulder width (P < 0.001 - P < 0.05) for all sequences. TrueFISP (r = 0.98, P < 0.001) was superior to EPI sequences (r = 0.88, P < 0.01 for SE EPI and r = 0.80, P < 0.05 for GE EPI). The images of all three sequences used were free of major motion artifacts. Fast and ultrafast sequences seem to be reliable for fetal shoulder measurements and the TrueFISP was the most accurate sequence compared to SE and GE echo-planar sequences. J. Magn. Reson. Imaging 2001;13:938-942.

Effects of diabetic pregnancy on the fetus and newborn.

Diabetes in pregnancy is unique because of the diversity of problems that can affect the embryo/fetus beginning with conception. Considerable effort has been devoted to understanding the basic developmental biology from observing young embryos in vitro or in vivo. Maternal glucose control has been identified as an important event. The preponderance of evidence indicates that rigid glucose control will minimize the incidence of anomalies incurred before 9 weeks of pregnancy. Later events are related to fetal hyperinsulinemia. These include fetal macrosomia, respiratory distress syndrome, neonatal hypoglycemia, neonatal hypocalcemia, and neonatal hypomagnesemia. Control of maternal metabolism can have a significant impact on each of the above. Finally, the long-term effects of maternal diabetes are as diverse as the pathogenetic events during pregnancy. Surprisingly, there is a significant transmission rate of 2% of type I diabetes if the mother has insulin-dependent diabetic mother, whereas the rate is 6% for the father. The Diabetes in Early Pregnancy Study showed that good maternal control was associated with normal neurodevelopmental outcome.

What is the significance of macrosomia?

This commentary/review briefly considers the diverse criteria recommended for classification of overweight infants. Macrosomia continues to be a vexing problem for both obstetricians and pediatricians. Among the various techniques possible for use in assessing body composition, none are more practical than body weight relative to gestational age. The criteria for normative data from large populations are reviewed. The stringent definition, i.e., exceeding +2 SD of an appropriate normative population, is reaffirmed. Using these criteria, infants of diabetic mothers showed a significant relationship of body weight to fetal hyperinsulinemia.

Leptin concentration in cord blood correlates with intrauterine growth.

Leptin is an adipocyte-derived peptide hormone regulating energy balance in experimental animals. Although the physiological function of leptin in humans is still unclear, its secretion is closely related to fat mass in adult humans. To examine how fetal growth correlates with leptin levels at birth, an umbilical cord venous blood sample was obtained at the delivery from 50 term newborn infants. Twenty-eight of the newborn infants had birth weights appropriate for gestational age (AGA; mean +/- SEM, 3362 +/- 90 g; relative birth weight, -0.08 +/- 0.2 SD), 9 were large for gestational age (birth weight, 4655 +/- 165 g; relative birth weight, 3.2 +/- 0.3 SD; P < 0.001 vs. AGA newborn infants), and 13 were small for gestational age (SGA; birth weight, 2385 +/- 69 g; relative birth weight, -2.2 +/- 0.08 SD; P < 0.001 vs. AGA newborn infants). Leptin concentrations were higher in large for gestational age (35.7 +/- 8.0 micrograms/L; P < 0.005), but lower in SGA (3.3 +/- 0.5 micrograms/L; P < 0.001) than in AGA infants (14.5 +/- 2.8 micrograms/L). When adjusted for differences in body weight, mean leptin levels were similar in the three newborn groups. Leptin concentration correlated closely with both absolute and relative birth weights (r = 0.71; P < 0.001 in both), with cord blood insulin concentration (r = 0.67; P < 0.001), and with placental weight (r = 0.60; P < 0.001). These data suggest that leptin is synthesized in utero, and that the circulating leptin concentration relates to the intrauterine growth pattern.

Acute asthma during pregnancy.

BACKGROUND: Acute asthma during pregnancy is potentially dangerous to the fetus. The aim of this study was to investigate the effect of an acute attack of asthma during pregnancy on the course of pregnancy or delivery, or the health of the newborn infant, and to identify undertreatment as a possible cause of the exacerbations. METHODS: Five hundred and four pregnant asthmatic subjects were prospectively followed and treated. The data on 47 patients with an attack of asthma during pregnancy were compared with those of 457 asthmatics with no recorded acute exacerbation and with 237 healthy parturients. RESULTS: Of 504 asthmatics, 177 patients were not initially treated with inhaled corticosteroids. Of these, 17% had an acute attack compared with only 4% of the 257 patients who had been on inhaled anti-inflammatory treatment from the start of pregnancy. There were no differences between the groups as to length of gestation, length of the third stage of labour, or amount of haemorrhage after delivery. No differences were observed between pregnancies with and without an exacerbation with regard to relative birth weight, incidence of malformations, hypoglycaemia, or need for phototherapy for jaundice during the neonatal period. CONCLUSIONS: Patients with inadequate inhaled anti-inflammatory treatment during pregnancy run a higher risk of suffering an acute attack of asthma than those treated with an anti-inflammatory agent. However, if the acute attack of asthma is relatively mild and promptly treated, it does not have a serious effect on the pregnancy, delivery, or the health of the newborn infant.

Hyperinsulinemia and macrosomia in the fetus of the diabetic mother.

OBJECTIVE: To determine 1) whether macrosomia in the fetus of the diabetic mother is related to fetal hyperinsulinemia and 2) whether hyperinsulinemia and macrosomia are related to maternal metabolic control. RESEARCH DESIGN AND METHODS: Normal pregnant women (n = 95) were compared with insulin-treated pregnant women (n = 155), who were subdivided according to White's class, hypertension, and mode of delivery. All women were treated to achieve optimal metabolic control. HbA1c was determined at each visit. At delivery, umbilical plasma was analyzed for glucose, insulin antibodies, total insulin, free insulin, C-peptide, proinsulin components, and total and individual amino acids. RESULTS: Macrosomia, defined as > 2 standard deviation units (97.75%), was found in 10-27% of the diabetic groups. It was not related to maternal mass or size, but was significantly correlated with umbilical total insulin, free insulin, and C-peptide. Proinsulin components were not different among groups. Amino acids also were not different. Glycosylated hemoglobin was a weak predictor of birth weight and fetal hyperinsulinism. CONCLUSIONS: Macrosomia in the fetus of the diabetic mother remains inadequately explained. In a large population of pregnant women with strict metabolic control, macrosomia was mainly independent of glycosylated hemoglobin. Nevertheless, fetal hyperinsulinism remains the driving force for excessive fetal growth. The stimulus for fetal insulin excess in humans remains to be defined.

Maternal alcohol abuse is associated with elevated fetal erythropoietin levels.

The erythropoietin levels in mixed cord serum of 40 infants born to drinking women were compared with those of 24 infants born to abstinent women. Twenty infants born to drinkers had signs of fetal alcohol effects. Thirty-five percent of the erythropoietin levels in mixed cord serum of infants of drinking mothers were above the normal range. Further, the elevation in fetal erythropoietin level correlated with maternal alcohol intake; infants of mothers consuming at least 300 g of ethanol weekly (28) had significantly higher (P less than .025) umbilical erythropoietin levels (median 66 mU/mL, range 10-2500) compared with infants of mothers consuming 150-300 g of ethanol weekly (median 37 mU/mL, range 23-215) or infants of control women (median 32 mU/mL, range 11-73). The subgroup analysis between infants with and without fetal alcohol effects showed no differences in umbilical erythropoietin levels. Maternal alcohol ingestion during pregnancy is associated with elevated umbilical erythropoietin levels, but whether this is a direct effect of ethanol or is induced by chronic fetal hypoxemia remains unclear.

Direct relationship of antepartum glucose control and fetal erythropoietin in human type 1 (insulin-dependent) diabetic pregnancy.

In the present study the antepartum relationship between maternal diabetic glucose control and fetal hypoxaemia was examined in 44 Type 1 (insulin-dependent) diabetic and 23 non-diabetic control pregnancies. Maternal HbA1C was used to assess maternal integrated blood glucose control while fetal metabolic control was evaluated by antepartum glucose, insulin, and C-peptide determinations in amniotic fluid at elective caesarean delivery. Fetal hypoxaemia was assessed indirectly by fetal umbilical vein plasma erythropoietin level at delivery. A prospectively developed statistical pathway model was used to examine the relationship of these variables. In applying forced stepwise multiple regression with this model, we observed in the diabetic subjects that mean maternal HbA1C during the last month of pregnancy correlated significantly with fetal umbilical venous erythropoietin at delivery (r = 0.57, p less than 0.001). Additional significant contributions to umbilical venous erythropoietin were found for amniotic fluid glucose and amniotic fluid insulin when these two independent variables were added in stepwise fashion (p less than 0.01). We conclude that in diabetic pregnancy, antepartum control of maternal hyperglycaemia is a significant factor associated with fetal hypoxaemia. We speculate that this effect is mediated through perturbations which accelerate fetal metabolism and which is expressed by amniotic fluid levels of glucose and insulin.

Amniotic fluid erythropoietin predicts fetal distress in Rh-immunized pregnancies.

Repeated amniotic fluid erythropoietin measurements in 23 Rh-immunized pregnancies were done to evaluate erythropoietin levels of amniotic fluid as an indicator of fetal distress (umbilical artery, pH 7.14 or less, or 1-minute Apgar score of 4 or less). Amniotic fluid erythropoietin levels did not vary significantly between 168 and 273 gestational days in the pregnancies without fetal distress. Increasing levels of amniotic fluid erythropoietin predicted highly reliably severe fetal distress at birth. Whether erythropoietin levels of amniotic fluid can also predict fetal distress in other pathologic pregnancies needs further study.

Effect of pregnancy on the electroencephalogram of epileptic women.

The electroencephalograms (EEGs) of epileptic women in late pregnancy were compared with their EEGs outside pregnancy and the puerperium. The number of epileptic interictal discharges was not modified by pregnancy. Visual scoring and frequency analysis demonstrated a slight increase in the alpha band during pregnancy. No correlations were found between the EEG findings and changes in seizure frequency.

Serum phenytoin during pregnancy, labor and puerperium.

111 pregnancies of epileptic women on phenytoin therapy were observed in a prospective study. Maternal serum phenytoin concentrations were measured monthly or bi-weekly during pregnancy, labor and puerperium. The concentration decreased towards the end of pregnancy and was lowest at delivery. In 48% of the patients the drug dosage had to be increased to combat the increased seizure frequency.

Amniotic fluid erythropoietin correlates with umbilical plasma erythropoietin in normal and abnormal pregnancy.

In the human fetus, elevated plasma erythropoietin levels have been found in high-risk pregnancies at delivery. We examined the relationship of amniotic fluid erythropoietin and umbilical plasma erythropoietin at delivery in 17 normal pregnancies, 41 hypertensive pregnancies, and 37 insulin-treated diabetic pregnancies terminated by elective cesarean section without labor. An additional 27 insulin-treated diabetic patients were studied after undergoing variable durations (86-1184 minutes) of labor. Erythropoietin was analyzed using a highly sensitive and specific radioimmunoassay technique. Fetal plasma erythropoietin concentrations were elevated above the control upper range (50.3 mU/mL) in 59% of the hypertensives and in 38% of the diabetics. The amniotic fluid erythropoietin values were significantly lower than the umbilical plasma erythropoietin values in each study group. Although the umbilical plasma erythropoietin values in the abnormal pregnancy groups differed considerably from the corresponding levels in the controls, the ratio of amniotic fluid erythropoietin to umbilical plasma erythropoietin was approximately the same in controls, hypertensives, and diabetics. Furthermore, the plasma and amniotic fluid levels (In transformed) correlated highly significantly in all three individual groups in absence of labor. In the diabetic labor group, this relationship was nonsignificant. We conclude that in the absence of labor, amniotic fluid erythropoietin reflects fetal plasma erythropoietin. We speculate that amniotic fluid erythropoietin may be an antepartum indicator of fetal hypoxemia.

Temporal response of immunoreactive erythropoietin to acute hypoxemia in fetal sheep.

Acute hypoxemia was produced in chronically catheterized sheep fetuses to determine the response time necessary to increase plasma immunoreactive erythropoietin (Ep) concentration. Sodium nitrite (0.2 mM) was infused via a fetal vein to induce fetal hypoxemia. The resultant fetal methemoglobinemia was associated with a predictable, incremental decrease in arterial oxygen content. Twelve nitrite infusions were performed in eight fetal sheep preparations (gestational ages 115-146 days). Mean methemoglobin level increased to 33% of total Hb after 1-2 h of NaNO2 infusion. These results were compared to those obtained in nine control studies in eight fetuses in which no change was observed for plasma Ep, arterial oxygen content, PaO2, pHa, or whole blood lactate. In the nitrite infused group, however, a significant and progressive increase in mean plasma Ep level over baseline levels was observed during the 4th and 5th h of hypoxemia (p less than 0.01). This change in Ep was significantly greater compared to the control group. These results, however, were confounded by the concomitant development of a lactic acidemia secondary to the fetal hypoxemia. To examine the theoretic possibility that lactic acidemia may primarily affect fetal Ep levels, an additional group of five fetuses was infused with L-lactic acid for the same time period. Although the decrements in pHa and whole blood lactate levels achieved in these fetuses were in excess of those observed during the nitrite infusions, this possibility was ruled out since no change in fetal plasma Ep levels occurred. We conclude that during the 4th h of acute fetal hypoxemia a predictable, progressive increase in plasma Ep level is observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of the interpretation of fetal heart rate records with cord plasma erythropoietin levels.

On the basis that fetal levels of plasma erythropoietin (Ep) may reflect fetal oxygenation the primary purpose of the present study was to assess the relation between Ep measured in cord plasma at delivery and the intrapartum fetal heart rate (FHR) record. A scoring system for interpreting FHR recordings blindly was prospectively utilized in 41 selected human pregnancies during the 4 h immediately preceding birth. The correlation of the overall mean FHR score for each individual patient with cord plasma Ep was significant such that the highest Ep levels were observed in those infants with the most abnormal FHR scores. Furthermore, when the birthweights of the infants were adjusted for gestational age, sex, and birth order, birthweight centile was negatively correlated with cord plasma Ep. When both FHR score and birthweight were simultaneously correlated with cord plasma Ep using multiple regression, the combined effect of these two factors improved the association of either alone with both contributing approximately equally.